Biomarkers in Heart Failure

Biomarkers are deeply incorporated into up-to-dated clinical guidelines for heart failure. There is evidence regarding the limiting role of biomarker as predictive tool in heart failure management. In fact, multiple biomarker strategy appears to be much more promising than those established on single biomarker measure or serial monitoring for circulating level of single biomarker.

Introduction
Heart Failure (HF) is considered a leading cause of cardiovascular (CV) death in patients with established CV disease [1]. Prevalence of HF has been exhibiting a strong tendency to growth worldwide, despite the scientific progress in the field of the two past decades. HF is also characterized by an elevated rate of primary and secondary hospitalization and increased economic burden for patients and their families. Although there are pretty numbers of clinical guidelines, which clearly indicated diagnosis, prevention and evidence-based treatment of HF, a strategy regarding exclusion of HF diagnosis, as well as risk stratification of HF, nature evolution of disease is not well established and requires more development [2]. Over the last decades, biological markers reflected several pathophysiological stages of HF with reduced (HFrEF), mid-regional (HFmrEF) and preserved (HFpEF) left ventricular (LV) ejection fraction (EF)have become a powerful and convenient noninvasive tool for diagnosis of HF, a stratification of HF patients at risk of progression, HF severity, and biomarker-guided therapy [3].

Conventionally used biomarkers
Currently updated clinical recommendations have been reported that the natriuretic peptides (NPs), including brain NP (BNP), mid-regional pro-atrial NP (MR-proANP), NT-pro-brain NP (NT-proBNP), mid-regional pro-brain NP (MR-proBNP), galectin-3,high-sensitivity cardiac troponins and soluble suppressor of tumorigenicity-2 (sST2)receptor are the most frequently used biomarkers in routine clinical practice to stratify patients at risk of HF development, a risk of admission / re-admission to the hospital due to HF-related reasons, and a risk of death. Most data on cardiac biomarkers have been derived from chronic HF individuals. In contrast, risk prediction in patients admitted with acutely decompensated HF (ADHF) remains a challenge [4].

Biomarker-guided therapy of HF
Biomarker(s)-guided therapy with serial biomarker values is considered a pretty reliable and as it is suggesting effective method for timely therapeutic adjustment in HF management. Although there are some speculations regarding strong evidence of biomarker-guided HF therapy, the proof-of-concept appears to be promising for individualizing medical care including rehabilitation in HF [5].As it had been suggested the biomarker(s)-guided HF therapy could improve a routine clinical management through adjusted doses/ routes of drug(s) and increase a competence regarding decision-making for an admission to the hospital before urgent state onset.NP guided HF therapy improves titration of medications. However, it has been found that BNP-guided therapy was not better than expert's clinical assessment for beta-blocker titration in chronic HF patients [6].Additionally, NT-proBNP, but not BNP, is better suited during HF therapy based on the new angiotensin-receptor-neprilysin-inhibitor (ARNI). Indeed, new era in use of NPs in monitoring of HF evolution has been opened after implementation in the routine clinical practice [7]. However, there are expectations regarding that the galectin-3- and pro-calcitonin-based HF therapies would be better than NP-guided treatment strategy in HFrEF / HFpEF.

Limitations in use of NPs in HF
Confusingly, the role of NPs in modification of treatment care considerably relates to aging, CV disease and metabolic co-morbidities, kidney clearance, metabolism (neprilysin for BNP, glycosylation, methylation, oxidation for other NPs), toxic effect (cardiotoxicity). Therefore, higher individual biological variability of these biomarkers may negatively effect on interpretation of measure results.Because of biologically active BNP is degraded by neprilysin, in HF patients treated with ARNI circulating level of BNP sufficiently increases, whereas NT-proBNP concentration declines dramatically. Apparently, monitoring of BNP levels is not suitable for risk stratification and HF adjusted medical care, when ARNIs are used, however, NT-proBNP remains to be a main key for initiated risk assessment and appraised HF stratification regardless drugs’ prescription.

Information gathered in the large randomized clinical trials presumably addressed to NPs and comprehensive meta-analyses have revealed that the goal of the HF therapy suggested as lowered biomarker concentration up 30% and more has not been achieved in the majority of the patients and could relate to HF phenotypes. Other leading limitations of NPs-guided therapy was pretty accurate, but fairly hard criteria of successful treatment of HF, high biological variation of NPs in several individuals with HFrEF, HFmrEF, HFpEF, co-existing comorbidities, such as obesity and older age, which influenced independently on NP concentrations. Therefore, evidence received from meta-analysis did not support a strong benefit for elderly HF patients treated with NPs-guided strategy versus conventional therapy. Consequently the hypothesis mentioned above has not really been tested and, unfortunately, it has not still incorporated into routine clinical practice. However, there is no strong evidence for clinically-proven data about this conception because there are findings for suboptimal sensitivity and/or specificity of HF management.

Galectin-3 or sST2: what’s better?
Although galectin-3 (Gal-3) is an independent predictor of all-cause mortality, CV death and occurrence of HF, there is an inverse relationship between serum galectin-3 and estimated glomerular filtration rate [8]. Therefore, older patients contributed to higher Gal-3 concentrations than younger individuals. Amongst other biomarkers (NPs, growth / differentiation factor [GDF]-15, high-sensitivity troponin T, sST2, aldosterone, phosphate, parathyroid hormone, plasma renin concentration, and creatinine) Gal-3 had the lowest indices of individual biological variability, whereas NPs and GDF-15 has the highest ones. In contrast to NPs serum Gal-3 levels did not appear to be significantly related to circulating level of cardiac troponins, LVEF and LV mass index [8]. Thus, Gal-3 and NPs might be allocated as the best tool for both short- and long term death prediction in HF regardless kidney function and age.

Optimistically results of recent clinical trial about higher predictive value of sST2 receptor in HF [6] have associated with some evidence regarding that sST2 was related to increased age, female sex, and some comorbidities including diabetes, atrial fibrillation, inflammatory diseases, kidney insufficiency and myocardial infarction. Additionally, sST2 was not associated with LV structure or LV systolic or diastolic function [8]. Thus, these findings confirmed that the sST2 is rather a systemic inflammatory marker of extra cardiac origin of HF deteriorations than a single prognosticator of HF evolution.

Additionally, there is no strong and clear evidence regarding that the new biomarkers are able to predict clinically significant end-points (i.e., all-cause and CV mortality, HF admission / re-admission, and HF death) in both HF phenotypes - HFpEF and HFrEF. Recent clinical trials have been revealed that majority of new biomarkers indicated rather HF phenotype-related clinical outcomes than independently predicted any end points regardless presentation of HFpEF / HFrEF. Probably, biomarker-based approach could be useful to characterize pathophysiological differences between HFrEF and HFpEF patients.

Multiple biomarker predictive scores
Multiple biomarkers’ use strategies based on the combination of NPs with other biomarkers have been discussed as priority in creating of much more accurate predictive scores in HF [7]. Although there are several predictive scores based on biomarker measurement and approved for chronic HF, predictive scores for and acutely decompensated HF have not been validated [8]. Current multiple biomarker score toward prognostication, risk stratification and diagnosis of HF is based on NPs in combination with biomarkers of myocardial injury and fibrosis (galectin-3 and sST2 receptor). It is validated by American Heart Association / American College of Cardiology at 2017 and the score is suitable for patients at risk of HF, individuals with established chronic HF (for both HFrEF and HFpEF), patients with suspected acute HF and documented acute / acutely decompensated HF, as well as patients with HF at discharge from the hospital. However, there is need to compare novel scores with recently created and the scores used in HFrEF and HFpEF to optimize the treatment approach in HF management [4].

Novel biomarkers
Recently developed biomarkers, i.e. mid-regional pro-A-type natriuretic peptide (Mid Pro-ANP), mid-regional-proadrenomedullin (MR-proADM), pro-endothelin, GDF-15, and copeptin, when were added to the predictive model based on well-known prognostic biomarkers (NPs, troponin, hs-CRP, pro-calcitonin), have been investigated in 28-days predictive value of entire score in patients with severe acute dyspnea and suspecting to acute HF or ADHF. Although three biomarkers - Mid Pro-ANP, MR-proADM and pro-endothelin - have been independently associated with prognosis of acute and chronic HF regardless LFEF, MR-proADM had improved discriminative value of NPs in combination with copeptin and troponin T [9]. There is no clarity and consistent evidence for multiple biomarker strategy in improvement in CV mortality and CV outcomes. It has been suggesting that sST2,MR-proADM and Gal-3 could improve prognostication of chronic HF-related hospitalization and death, when they are added to NPs. Additionally, not only the diagnosis of acute HF itself but the evaluation of co-morbidities using markers like NPs, Gal-3, sST2 or acute kidney injury markers presents a new perspective to the management of acute HF or actually decompensated HF. Probably, co-morbidities especially diabetes mellitus play a pivotal role in modulation of distinct profile of widely used biomarkers in HF as chronic as well as acute HF or ADHF. In this context, the discovery of brand new approaches based on biomarker measurement could be promised for improving HF diagnosis and care.

In conclusions, the increased biological variability, presence of co-morbidities, age- and sex-related particularities, as well as extended diagnostic “grey zone” for single and serial measured biomarkers (i.e. NPs, sST2, galectin-3) make to discover more diagnostically accurate and prognostically powerful biomarkers. In this context, metabolic disturbance, which is remarkable in patients with different phenotypes of HF, might demonstrate powerful diagnostic and predictive values facilitating optionally used clinical-based and biomarkers-related predictive scores. There are several controversies regarding importance of predictive value for survival and incremental prognostication in diagnosis of HFrEF and HFpEF. Probably, biomarkers of inflammation and vascular remodeling are predominantly observed in HFpEF, while biomarkers of biomechanical stress and collagen metabolism much more accurately predicted clinical outcome in HFrEF. All these require improving clinical guideline recommendations for optimising HF therapy in routine clinical practice under biomarkers’ control. There is need in larger clinical trials to head-to-head compare different biomarkers and clear their role in diagnosis and guided therapy of HF.

Acknowledgement
Ethics approval and consent to participate: Not applicable
Consent for publication: Alexander Berezin is sole author of the paper and gives a consent for publication
Availability of data and materials: Not applicable
Competing interests: Not declared
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors

Dr. Alexander E. Berezin has received PhD in 1994 in the State Medical University of Zaporozhye (Ukraine). He is currently working as a Professor of Medicine in the State Medical University of Zaporozhye (Ukraine). His research goals are fundamental study of biological markers, the development of cardiovascular prevention and rehabilitation. Based on this research and training in heart failure he has received several awards and honors. He has published 850 papers and more in reputed journals, 27 books/chapters and has been serving as an editorial board member of repute.